EP2305288B1 - Préparations d'insuline amères dotées d'une stabilité améliorée - Google Patents
Préparations d'insuline amères dotées d'une stabilité améliorée Download PDFInfo
- Publication number
- EP2305288B1 EP2305288B1 EP10178842.0A EP10178842A EP2305288B1 EP 2305288 B1 EP2305288 B1 EP 2305288B1 EP 10178842 A EP10178842 A EP 10178842A EP 2305288 B1 EP2305288 B1 EP 2305288B1
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- EP
- European Patent Office
- Prior art keywords
- insulin
- polysorbate
- pharmaceutical formulation
- days
- present
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the invention relates to a pharmaceutical formulation containing a polypeptide selected from a group containing insulin, an insulin metabolite, an insulin analogue, an insulin derivative or combinations thereof; one surfactant or combinations of several surfactants; optionally one preservative or combinations of several preservatives; and optionally an isotonizing agent, buffer or other auxiliary substances or combinations thereof, wherein the pharmaceutical formulation has a pH in the acidic range.
- a pharmaceutical formulation containing a polypeptide selected from a group containing insulin, an insulin metabolite, an insulin analogue, an insulin derivative or combinations thereof; one surfactant or combinations of several surfactants; optionally one preservative or combinations of several preservatives; and optionally an isotonizing agent, buffer or other auxiliary substances or combinations thereof, wherein the pharmaceutical formulation has a pH in the acidic range.
- diabetes mellitus Around 120 million people worldwide suffer from diabetes mellitus. Among them are about 12 million type I diabetics, for whom the replacement of the missing endocrine insulin secretion is the only therapy currently possible. Those affected are dependent on insulin injections for life, usually several times a day. In contrast to type I diabetes, type II diabetes is not fundamentally deficient in insulin, but in a large number of cases, especially in the advanced stage, treatment with insulin, possibly in combination with an oral antidiabetic, is the cheapest form of therapy viewed. In healthy people, insulin release through the pancreas is strictly linked to the concentration of blood glucose. Increased blood glucose levels, such as occur after meals, are quickly compensated for by a corresponding increase in insulin secretion.
- the plasma insulin level drops to a basal value, which is sufficient to ensure a continuous supply of glucose to insulin-sensitive organs and tissues keep hepatic glucose production low at night.
- the replacement of the body's own insulin secretion with exogenous, mostly subcutaneous application of insulin generally does not come close to the quality of the physiological regulation of blood glucose described above. Blood glucose is often derailed up or down, which in its most severe forms can be life-threatening. In addition, however, blood glucose levels that have risen for years without initial symptoms pose a significant health risk.
- the large-scale DCCT study in the USA The Diabetes Control and Complications Trial Research Group (1993) N. Engl. J. Med.
- Late diabetic damage is micro- and macro-vascular damage, which may manifest itself as retino-, nephro- or neuropathy and lead to blindness, kidney failure and the loss of extremities and is also associated with an increased risk of cardiovascular diseases. From this it can be deduced that an improved therapy for diabetes must primarily aim to keep blood glucose as narrow as possible in the physiological range. According to the concept of intensified insulin therapy, this should be achieved by injecting fast and slow-acting insulin preparations several times a day. Rapid-acting formulations are added to meals to compensate for the postprandial increase in blood glucose. Slow-acting basal insulins are designed to ensure basic insulin supply, especially during the night, without leading to hypoglycemia.
- Insulin is a polypeptide of 51 amino acids, which are distributed over 2 amino acid chains: the A chain with 21 amino acids and the B chain with 30 amino acids. The chains are linked by two disulfide bridges. Insulin preparations have been used for diabetes therapy for many years. Not only naturally occurring insulins are used, but recently also insulin derivatives and analogs.
- Insulin analogs are analogs of naturally occurring insulins, namely human insulin or animal insulins, which are at least replaced by substitution distinguish a naturally occurring amino acid residue with other amino acids and / or addition / removal of at least one amino acid residue from the corresponding, otherwise identical, naturally occurring insulin. It can also be amino acids that do not occur naturally.
- Insulin derivatives are derivatives of naturally occurring insulin or an insulin analogue, which are obtained by chemical modification.
- the chemical modification can e.g. consist in the addition of one or more specific chemical groups to one or more amino acids.
- insulin derivatives and insulin analogues have a somewhat different effect than human insulin.
- Insulin analogues with accelerated onset of action are in EP 0 214 826 , EP 0 375 437 and EP 0 678 522 described.
- EP 0 124 826 relates among other things to substitutions of B27 and B28.
- EP 0 678 522 describes insulin analogs which have different amino acids, preferably proline, in position B29, but not glutamic acid.
- EP 0 375 437 includes insulin analogs with lysine or arginine in B28, which may optionally be additionally modified in B3 and / or A21.
- insulin derivatives and insulin analogues have a somewhat different effect than human insulin.
- Insulin analogs are described in which at least one amino acid of positions B1-B6 is replaced by lysine or arginine. Such insulins have according to WO 92/00321 an extended effect on. Delayed effects are also shown in the EP-A 0 368 187 described insulin analogues.
- the insulin preparations on the market of naturally occurring insulins for insulin substitution differ in the origin of the insulin (eg cattle, pork, human insulin) and the composition, with which the action profile (onset and duration of action) can be influenced. By combining different insulin preparations, a wide variety of activity profiles can be achieved and physiological blood sugar levels can be set if possible.
- the recombinant DNA technology nowadays enables the production of such modified insulins.
- Insulin glargine Gly (A21) -Arg (B31) -Arg (B32) -human insulin
- Insulin glargine is injected as an acidic, clear solution and, due to its solution properties, precipitates as a stable hexamer association in the physiological pH range of the subcutaneous tissue.
- Insulin glargine is injected once a day and is distinguished from other long-acting insulins by its flat serum profile and the associated reduction in the risk of nocturnal hypoglycaemia (Schubert-Zsilavecz et al., 2: 125-130 (2001)).
- insulin glargine which leads to the prolonged duration of action, is characterized by a clear solution with an acidic pH.
- insulins show a reduced stability and an increased tendency to aggregate under thermal and physical-mechanical stress, which can be noticeable in the form of cloudiness and precipitation (particle formation), especially at an acidic pH value ( Brange et al., J. Ph. Sci 86: 517-525 (1997 )).
- the tendency to aggregate can also be promoted by hydrophobic surfaces that are in contact with the solution ( Sluzky et al., Proc.Natl.Acad.Sci. 88: 9377-9381 (1991 ).
- the glass vessels of the preparations, the stopper material of the closure caps or the interface of the solution with the air supernatant can be considered as hydrophobic surfaces.
- the finest droplets of silicone oil can act as additional hydrophobic aggregation nuclei when the daily insulin dose is withdrawn using commercially available, siliconized insulin syringes and accelerate the process.
- WO 01/43762 describes aqueous, parenteral pharmaceutical preparations containing a polypeptide and glycerin, in which the stabilization of the preparation is to be achieved by cleaning off destabilizing constituents of the glycerol.
- WO 00/23098 describes insulin preparations stabilized with polysorbate 20 or poloxamer 188 for pulmonary application, but does not describe stabilization in acid solution against aggregation germs.
- the present invention was therefore based on the object of finding preparations for acid-soluble insulins with surfactants which are distinguished by a high long-term stability against stresses caused by temperature or physico-mechanical stress and which tolerate a high stress with hydrophobic aggregation germs.
- the pharmaceutical preparations contain 60-6000 nmol / ml, preferably 240-3000 nmol / ml of a Gly (A21), Arg (B31), Arg (B32) human insulin.
- the surfactants are present in the pharmaceutical composition in a concentration of 5-200 ⁇ g / ml, preferably 5-120 ⁇ g / ml and particularly preferably 20-75 ⁇ g / ml.
- the preparation can also contain preservatives (e.g. phenol, cresol, parabens), isotonizing agents (e.g. mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, glycerol). Contain buffer substances, salts, acids and bases as well as other auxiliary substances. These substances can each be present individually or as mixtures.
- preservatives e.g. phenol, cresol, parabens
- isotonizing agents e.g. mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, glycerol.
- Glycerol, dextrose, lactose, sorbitol and mannitol are usually present in the pharmaceutical preparation in a concentration of 100-250 mM, NaCl in a concentration up to 150 mM.
- Buffer substances e.g. Phosphate, acetate, citrate, arginine, glycylglycine or TRIS (ie 2-amino-2-hydroxymethyl-1,3, propanediol) buffers and corresponding salts are in a concentration of 5-250 mM, preferably 10-100 mM available.
- Other excipients can include salts or arginine.
- compositions of proteins or peptides for administration through membranes which show low toxicity and efficient permeation containing a mixture of a bile acid salt or fusidate with a nonionic detergent.
- the invention therefore relates to a pharmaceutical formulation according to claim 1.
- Such a pharmaceutical formulation is preferred, in which the preservative is selected from a group comprising phenol, cresol, parabens; wherein the isotonizing agent is selected from a group containing mannitol, sorbitol, sodium chloride, glycerol; the excipients are selected from a group containing buffer substances, acids, alkalis.
- the preservative is selected from a group comprising phenol, cresol, parabens
- the isotonizing agent is selected from a group containing mannitol, sorbitol, sodium chloride, glycerol
- the excipients are selected from a group containing buffer substances, acids, alkalis.
- Another object of the invention is a pharmaceutical formulation as described above, in which the insulin, the insulin analogue, the active insulin metabolite and / or the insulin derivative in a concentration of 60-6000 nmol / ml, preferably in a concentration of 240-3000 nmol / ml is present (this corresponds to a concentration of 1.4 - 35 mg / ml or 40 - 500 units / ml); in which the surfactant is present in a concentration of 5-200 ⁇ g / ml, preferably 5-120 ⁇ g / ml and particularly preferably 20-75 ⁇ g / ml.
- Another object of the invention is a pharmaceutical formulation as set out above, in which glycerol and / or mannitol is present in a concentration of 100-250 mM, and / or NaCl preferably in a concentration up to 150 mM.
- Another object of the invention is a pharmaceutical formulation as set out above, in which a buffer substance is present in a concentration of 5-250 mM.
- Another object of the invention is a pharmaceutical insulin formulation which contains further additives, such as salts, which delay the release of insulin. Mixtures of such retardinsulins with the formulations described above are also included. Another object of the invention is a method for producing such pharmaceutical formulations. Another object of the invention is the use of such formulations for the treatment of diabetes mellitus. Another object of the invention is the use or addition of surfactants as a stabilizer during the manufacturing process of insulin, insulin analogues or insulin derivatives or their preparations. In the following, the application is described with the aid of a few examples, which are in no way intended to be restrictive.
- Example 1 Stabilization of the period of use of insulin glargine with polysorbate 20 (Tween® 20)
- the stabilizing effect of polysorbate 20 remains for a period of 3 months even when stored at elevated temperatures.
- a decrease in the stabilizing effect due to possible hydrolysis of the polysorbate in the acidic environment of the solution cannot be determined in comparison with the data after 1 month of storage.
- Example 2 Stabilization of Insulin Glargine with Polysorbate 20 under Physical-Mechanical Stress
- the samples are stored at + 5 ° C, 25 ° C and 37 ° C for a specified period. 5 samples are then subjected to a shake test. The results are shown in the table below, the limit 15 FNU corresponds to turbidity that can be seen in daylight.
- FNU Test sample 0 days 0.5 days 1 day 2 days 3 days 4 days 6 days 8 days 10 days Insulin glargine 0 0 0 2nd 3rd 3rd 4th 4th 4th Insulin glargine + 0.010 mg / ml polysorbate 20 0 0 0 0 0 1 3rd 4th 5 Insulin glargine + 0.015 mg / ml polysorbate 20 0 0 0 0 0 0 0 0 Insulin glargine + 0.020 mg / ml polysorbate 20 0 0 0 0 0 0 0 0 Insulin glargine + 0.030 mg / ml polysorbate 20 0 0 0 0 0 0 0 0 0 Number of vials> 15 FNU Test sample 0 days 0.5 days 1 day 2 days 3 days 4 days 6 days 8 days 10 days Insulin
- polysorbate 20 If polysorbate 20 is not added, visible turbidity can appear in the solution after only 2 days of severe physical and mechanical stress. By adding polysorbate 20, the formation of haze during physical-mechanical stress can be significantly delayed.
- the stabilizing effect of polysorbate 20 remains even when stored at elevated temperatures.
- a weakening of the stabilizing effect due to possible hydrolysis of the polysorbate in the acidic environment of the solution cannot be determined.
- Example 3 Comparison of the stabilization of the in-use period of insulin glargine with polysorbate 20 (Tween® 20) and with polysorbate 80 (Tween® 20)
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
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- Emergency Medicine (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Claims (12)
- Formulation pharmaceutique contenant de la Gly(A21), Arg(B31), Arg(B32)-insuline humaine et un tensioactif choisi dans un groupe contenant le Tween® 20 et le Tween® 80 ;
la formulation pharmaceutique étant une solution limpide qui présente une valeur de pH dans le domaine acide (pH 3,5 à 4,5). - Formulation pharmaceutique selon la revendication 1, un conservateur choisi dans un groupe contenant le phénol, le crésol, le chlorocrésol, l'alcool benzylique, les parabènes, étant contenu.
- Formulation pharmaceutique selon l'une quelconque des revendications 1 et 2, un agent d'isotonie choisi dans un groupe contenant le mannitol, le sorbitol, le lactose, le dextrose, le tréhalose, le chlorure de sodium, le glycérol, étant contenu.
- Formulation pharmaceutique selon l'une quelconque des revendications 1 à 3, un auxiliaire choisi dans un groupe contenant des substances tampon comme par ex. le TRIS, un phosphate, un citrate, un acétate, la glycylglycine ou d'autres substances telles que des acides, des solutions alcalines, des sels, étant contenu.
- Formulation pharmaceutique selon l'une quelconque des revendications précédentes, dans laquelle l'analogue d'insuline est présent en une concentration de 60 à 6 000 nmole/ml.
- Formulation pharmaceutique selon la revendication 8, l'analogue d'insuline étant présent en une concentration de 240 à 3 000 nmole/ml.
- Formulation pharmaceutique selon l'une quelconque des revendications précédentes, dans laquelle le tensioactif est présent en une concentration de 5 à 200 pg/ml.
- Formulation pharmaceutique selon la revendication 7, dans laquelle le tensioactif est présent en une concentration de 5 à 120 pg/ml.
- Formulation pharmaceutique selon la revendication 8, dans laquelle le tensioactif est présent en une concentration de 20 à 75 pg/ml.
- Formulation pharmaceutique selon l'une ou plusieurs des revendications 4 à 9, dans laquelle du glycérol et/ou du mannitol est/sont présent(s) en une concentration de 100 à 250 mM.
- Formulation pharmaceutique selon la revendication 10, dans laquelle NaCl est présent en une concentration allant jusqu'à 150 mM.
- Formulation pharmaceutique selon l'une quelconque des revendications précédentes, dans laquelle une substance tampon est présente en une concentration de 5 à 250 mM.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10227232A DE10227232A1 (de) | 2002-06-18 | 2002-06-18 | Saure Insulinzubereitungen mit verbesserter Stabilität |
PCT/EP2003/005887 WO2003105888A1 (fr) | 2002-06-18 | 2003-06-05 | Preparations acides d'insuline ayant une meilleure stabilite |
EP03732536A EP1517697B1 (fr) | 2002-06-18 | 2003-06-05 | Preparations acides d'insuline ayant une meilleure stabilite |
Related Parent Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03732536A Division EP1517697B1 (fr) | 2002-06-18 | 2003-06-05 | Preparations acides d'insuline ayant une meilleure stabilite |
EP03732536A Division-Into EP1517697B1 (fr) | 2002-06-18 | 2003-06-05 | Preparations acides d'insuline ayant une meilleure stabilite |
EP03732536.2 Division | 2003-06-05 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP20177930.3 Division-Into | 2020-06-03 |
Publications (3)
Publication Number | Publication Date |
---|---|
EP2305288A2 EP2305288A2 (fr) | 2011-04-06 |
EP2305288A3 EP2305288A3 (fr) | 2013-12-11 |
EP2305288B1 true EP2305288B1 (fr) | 2020-07-15 |
Family
ID=29723248
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03732536A Expired - Lifetime EP1517697B1 (fr) | 2002-06-18 | 2003-06-05 | Preparations acides d'insuline ayant une meilleure stabilite |
EP10178842.0A Expired - Lifetime EP2305288B1 (fr) | 2002-06-18 | 2003-06-05 | Préparations d'insuline amères dotées d'une stabilité améliorée |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03732536A Expired - Lifetime EP1517697B1 (fr) | 2002-06-18 | 2003-06-05 | Preparations acides d'insuline ayant une meilleure stabilite |
Country Status (38)
Country | Link |
---|---|
US (4) | US20040048783A1 (fr) |
EP (2) | EP1517697B1 (fr) |
JP (2) | JP5237522B2 (fr) |
KR (1) | KR101040029B1 (fr) |
CN (2) | CN102133393B (fr) |
AR (1) | AR039688A1 (fr) |
AU (1) | AU2003238471B2 (fr) |
BR (1) | BRPI0311877B8 (fr) |
CA (1) | CA2490116C (fr) |
CR (1) | CR7614A (fr) |
CY (1) | CY1113537T1 (fr) |
DE (1) | DE10227232A1 (fr) |
DK (1) | DK1517697T3 (fr) |
EC (1) | ECSP045496A (fr) |
ES (2) | ES2817879T3 (fr) |
HN (1) | HN2003000184A (fr) |
HR (1) | HRP20041200B1 (fr) |
IL (1) | IL165788A (fr) |
MA (1) | MA27205A1 (fr) |
ME (1) | MEP28708A (fr) |
MX (1) | MXPA04012233A (fr) |
MY (1) | MY142354A (fr) |
NO (1) | NO328567B1 (fr) |
NZ (1) | NZ537211A (fr) |
OA (1) | OA12870A (fr) |
PA (1) | PA8575701A1 (fr) |
PE (1) | PE20040560A1 (fr) |
PL (1) | PL208773B1 (fr) |
PT (2) | PT2305288T (fr) |
RS (1) | RS52388B (fr) |
RU (1) | RU2313362C2 (fr) |
SV (1) | SV2004001556A (fr) |
TN (1) | TNSN04249A1 (fr) |
TW (1) | TWI315201B (fr) |
UA (1) | UA79477C2 (fr) |
UY (1) | UY27854A1 (fr) |
WO (1) | WO2003105888A1 (fr) |
ZA (1) | ZA200409273B (fr) |
Families Citing this family (81)
Publication number | Priority date | Publication date | Assignee | Title |
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DE10227232A1 (de) * | 2002-06-18 | 2004-01-15 | Aventis Pharma Deutschland Gmbh | Saure Insulinzubereitungen mit verbesserter Stabilität |
AU2005222613B2 (en) * | 2004-03-12 | 2009-12-17 | Biodel, Inc. | Rapid acting drug delivery compositions |
WO2005115303A1 (fr) * | 2004-05-24 | 2005-12-08 | Wockhardt Limited | Purification d'un materiau du type insuline par chromatographie en phase inverse |
UA75030C2 (en) * | 2005-11-30 | 2006-03-15 | Viktor Oleksandrovych Bykov | Method for obtaining stable aqueous solutions of drugs |
WO2007135117A2 (fr) * | 2006-05-24 | 2007-11-29 | Novo Nordisk A/S | Formulations solubles stables contenant de l'insuline |
DE102006031962A1 (de) | 2006-07-11 | 2008-01-17 | Sanofi-Aventis Deutschland Gmbh | Amidiertes Insulin Glargin |
DE102006031955A1 (de) | 2006-07-11 | 2008-01-17 | Sanofi-Aventis Deutschland Gmbh | Verfahren zur Herstellung von Insulinanaloga mit dibasischem B-Kettenende |
EP2152243A2 (fr) * | 2007-04-30 | 2010-02-17 | Novo Nordisk A/S | Solutions et compositions hautement concentrées en insuline |
AU2009204309B2 (en) * | 2008-01-04 | 2012-11-22 | Biodel, Inc. | Insulin formulations for insulin release as a function of tissue glucose levels |
BRPI0907371A2 (pt) | 2008-01-09 | 2015-11-24 | Sanofi Aventis Deutschland | derivados de insulina com um perfil de tempo-ação muito retardado |
NZ586589A (en) | 2008-01-09 | 2012-04-27 | Sanofi Aventis Deutschland | Novel insulin analogues having an extremely delayed time-action profile |
CA2735581C (fr) * | 2008-08-29 | 2017-05-30 | Genzyme Corporation | Formulations de peptide a liberation controlee |
WO2010028055A1 (fr) * | 2008-09-02 | 2010-03-11 | Biodel, Inc. | Insuline dotée d’un profil de libération basal |
DK2349324T3 (en) | 2008-10-17 | 2017-12-11 | Sanofi Aventis Deutschland | COMBINATION OF AN INSULIN AND A GLP-1 AGONIST |
US9060927B2 (en) * | 2009-03-03 | 2015-06-23 | Biodel Inc. | Insulin formulations for rapid uptake |
ES2614161T3 (es) * | 2009-07-06 | 2017-05-29 | Sanofi-Aventis Deutschland Gmbh | Preparados acuosos de insulina que comprenden metionina |
KR101836070B1 (ko) | 2009-11-13 | 2018-03-09 | 사노피-아벤티스 도이칠란트 게엠베하 | Glp-1 작용제, 인슐린 및 메티오닌을 포함하는 약제학적 조성물 |
JP5973918B2 (ja) | 2009-11-13 | 2016-08-23 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Glp−1アゴニスト及びメチオニンを含む薬学的組成物 |
TW201138808A (en) | 2010-05-03 | 2011-11-16 | Bristol Myers Squibb Co | Serum albumin binding molecules |
US8637458B2 (en) | 2010-05-12 | 2014-01-28 | Biodel Inc. | Insulin with a stable basal release profile |
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- 2003-06-05 EP EP03732536A patent/EP1517697B1/fr not_active Expired - Lifetime
- 2003-06-05 CN CN201110056210.9A patent/CN102133393B/zh not_active Expired - Lifetime
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